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Questions and Answers on Gadolinium-Containing Contrast Agents 12/22/2006

This information is out-of-date. For updated information, please see Information on Gadolinium-Containing Contrast Agents. (5/2007)


1.  What information is new since the Questions and Answers from June 2006?

FDA’s previous information was limited to 25 cases in patients that received Omniscan for Magnetic Resonance Angiography (MRA) at doses higher than approved and recommended for Magnetic Resonance Imaging (MRI).

FDA has received an additional 65 case reports of Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) in patients who received Magnevist, Omniscan, and OptiMARK for MRI and MRA.

NSF/NFD has now been reported in patients who received the recommended doses of the contrast agents.

Researchers have found gadolinium deposits in the skin of patients who developed NSF/NFD.

2. What is gadolinium and what is its use in clinical medicine?

Gadolinium is a paramagnetic metal ion. Paramagnetic ions, such as gadolinium, tend to move into magnetic fields. This trait makes paramagnetic ions such as gadolinium useful for MRI and MRA.

Gadolinium-based contrast agents are manufactured by a chelating process, a procedure in which large organic molecules form a stable complex around the gadolinium. The chelate reduces the chances of toxicity that could result from exposure to free gadolinium. This stable complex is eliminated via the kidneys in patients with normal functioning kidneys.

Gadolinium-based contrast agents are approved by FDA for use with MRI as a contrast agent to provide an improved image of body organs and tissues.

Gadolinium-based contrast agents are also used for MRA, another imaging procedure used to evaluate blood vessels.

3. What is the difference between MRA and MRI?

MRA is a special type of MRI used to study blood vessels. MRA is utilized to aid in the detection of heart disorders, stroke, and vascular diseases.

4. Can an MRI and MRA be performed without gadolinium-based contrast?

Yes, MRI and MRA can be performed without contrast.

MRI with gadolinium-based contrast agents provides additional diagnostic information as compared to MRI without contrast.  

The use of gadolinium-based contrast agents in MRA is not FDA approved. MRA with gadolinium-based contrast is thought by many radiologists to provide more detailed images of blood vessels than MRA without gadolinium-based contrast.  

5. Are there any FDA approved MRA contrast agents?

No.

6. Are there other approved MRI contrast agents that do not contain gadolinium?

Yes. However, the two other approved MRI contrast agents, Feridex, I.V. (an iron-containing injectable solution) and Teslascan (a manganese-containing injectable solution) are FDA-approved only for the evaluation of lesions of the liver. Imaging contrast agents, such as iodinated contrast agents are used in Computed Tomography, plain X-ray and X-ray angiography. However, these iodinated contrast agents require X-ray imaging rather than MRI.

7. What is the concern regarding gadolinium-based contrast agents?

Patients with moderate (glomerular filtration rate less than 60 mL/min/1.73m2) to end-stage (glomerular filtration rate less than 15 mL/min/1.73m2 or on dialysis) kidney disease who receive gadolinium-based contrast agents are at risk for developing a serious systemic fibrosing disease called Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD).

As of December 21, 2006, FDA has received 90 reports of NSF/NFD in patients who received gadolinium-based contrast agents for MRI and MRA.  In addition, researchers have found gadolinium deposits in the skin of patients with NSF/NFD.  The association between NSF/NFD was first reported in a May 29, 2006, press release from the Danish Medicines Agency (DMA) and the April 2006 report by Grobner et al in Nephrology, Dialysis and Transplantation (2006) Vol 21 (4):1104-1108 and following erratum (2006) 21(6): 1745.

8. What is Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD)?

NSF/NFD was first described in the medical literature in 2000. The first case of NSF/NFD was identified in 1997. The disease is observed in patients that have moderate to end-stage kidney disease.  NSF/NFD causes fibrosis of the skin and connective tissues throughout the body. Patients develop skin thickening that may prevent bending and extending joints, resulting in decreased mobility of joints. NSF/NFD usually starts in the lower extremities. Fibrosis can also develop in the diaphragm, muscles in the thigh and lower abdomen, and lung vessels. The clinical course of NSF/NFD is progressive and may be fatal.

9. What is the treatment for NSF/NFD?

There is no known treatment for NSF/NFD.

Improved renal function (spontaneous or via renal transplantation) appears to slow or arrest NSF/NFD and may even result in a gradual reversal of NSF/NFD.  Other treatments are being tested. 

10. How many gadolinium-based contrast agents has FDA approved? Was NSF/NFD seen with all of the U.S.-approved gadolinium-based contrast agents?

There are five FDA approved gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance).

Of the 90 cases of NSF/NFD FDA has received, most have been associated with the administration of Omniscan. Other cases, however, have been associated with Magnevist and OptiMARK exposure.  Although NSF/NFD has been reported for only 3 of the 5 gadolinium-based contrast agents, FDA believes that NSF/NFD may occur with the use of any of the approved gadolinium-based contrast agents.

11. Do the gadolinium-based contrast agents cause NSF/NFD?

Whether the gadolinium-based contrast agents are the only agents or conditions that may be associated with NSF/NFD in patients with renal disease is unknown.  However, the 90 case reports FDA has received and the finding of gadolinium deposits in the skin of patients with NSF/NFD suggests that gadolinium-based contrast is a factor in the development of NSF/NFD in patients with moderate to end-stage kidney disease.   

12. What actions will FDA take regarding the new information about gadolinium-based contrast agent administration and the development of NSF/NFD in patients with moderate to severe kidney disease?

FDA is continuing to evaluate the 90 case reports, is having ongoing discussions with NSF/NFD experts, is reviewing results of clinical trials with gadolinium-based contrast agents, and is working with the manufacturers to review all safety reports and adverse event reports. FDA will be initiating labeling changes for gadolinium-based contrast agents.

13. What information was known about serious side effects prior to the approval of gadolinium-based contrast agents?

The five U.S. approved gadolinium-based contrast agents were approved between 1988 and 2004.  In the combined pre-marketing studies for these approved gadolinium-based contrast agents, over 3000 patients were studied.

The most common serious side effect from gadolinium-based contrast agents is an allergic reaction that is usually mild but is occasionally severe and even results in fatalities.  Some patients develop skin conditions, such as rash, sweating, itching, hives, and facial swelling.  Most of these conditions are allergic in nature.

Gadolinium-based contrast agents can be very irritating to the veins into which they are injected, causing irritation of blood vessels and skin and the formation of blood clots.

Very few patients with severely compromised kidney function or those on dialysis have been studied in clinical trials. The labels for gadolinium-based contrast agents caution that the risk of toxic reactions may be greater in patients with impaired kidney function because gadolinium is mostly excreted by the kidney.

14. What should patients do with this new information?

If you have moderate to end-stage kidney disease and a physician has requested an MRI or MRA study with a contrast agent, ask if there are other contrast agents that could be used or other diagnostic tests that could be done. If gadolinium-containing contrast agents are necessary, physicians and patients should carefully select the contrast agent based on the individual patient’s medical care needs.

If you have moderate to end-stage kidney disease and you received a gadolinium-based contrast MRA, you should tell your doctor.

Call your doctor right away if any time after your gadolinium injection you get any of these conditions

  • Skin and eyes
    • Swelling, hardening and tightening of your skin
    • Reddened or darkened patches on the skin
    • Burning or itching of your skin
    • Yellow raised spots on the whites of your eyes
  • Bones and muscles
    • Stiffness in your joints; problems moving or straightening arms, hands, legs, or feet
    • Pain deep in your hip bones or ribs
    • Muscle weakness

15. What should healthcare providers do in response to this new information?

Physicians should consider the risks and benefits of using gadolinium-based contrast agents for MRI or MRA in patients with moderate to end-stage kidney disease.  If such a patient receives gadolinium-based contrast agent, the physician should consider prompt dialysis. Physicians should also report all cases of NSF/NSD to the FDA’s MedWatch program either online, by regular mail or by fax, using the contact information at the bottom of this page.

16. What additional actions are likely to follow?

FDA will complete its ongoing analysis of these preliminary findings and then consider multiple options such as: modifying the product label or requiring additional studies. FDA may also consider other risk management options.

17. Where can I find more information about gadolinium-based agents and about NSF/NFD?

The package inserts provide more information about all of the approved gadolinium-based agents. More information about NSF/NFD can be found at the following website: http://www.pathmax.com/dermweb/.
 

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